Abstract The overarching goal of this application is to development a novel immunotherapy for treatment of metastatic prostate cancer (mPC), a lethal with limited treatment options. Immunotherapy has significantly improved survival in patients with a variety of solid tumors, however it has only presented limited efficacy in metastatic prostate cancer patients. Thus, there is an unmet need to develop effective immunotherapies for mPC. Based on the findings that metastatic prostate tumor cells convert the stress-induced immune stimulatory cell surface molecule, the MHC I Chain related molecule (MIC), to a highly immune suppressive soluble MIC (sMIC). CanCure has developed a first-in-class sMIC-targeting monoclonal antibody (mAb) B10G5 that has demonstrated remarkable efficacy in eliminating prostate metastatic as a single agent in preclinical models. When used in combination, B10G5 synergizes with immune checkpoint blockade therapy and eliminates immune checkpoint therapy-induced colon toxicity. We show that B10G5 confers its therapeutic efficacy through two defined mechanisms of action. CanCure has formulated the B10G5 mAb for human use (designated and huB10G5) and tested the safety of huB10G5 in pilot toxicity study in non-human primates (NHP). HuB10G5 is ready for IND-enabling studies. To achieve our goal, CanCure proposes two specific Aims: 1) Determine therapeutic efficacy of B10G5 with frontline AR-targeting therapy for mPC; 2) Conduct pre-clinical IND-enabling GLP production and toxicology study. The outcome of proposed study would define the path and provide a strong scientific rationale on how to translate our new therapy into early clinical trials. .